Embolic coils

ABSTRACT

Coils, such as embolic coils, and related methods, devices, and compositions, are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of, and claims priority under35 U.S.C. § 120 to, U.S. patent application Ser. No. 11/311,617, filedon Dec. 19, 2005, and entitled “Coils”, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The invention relates to coils, such as embolic coils, as well asrelated methods, devices, and compositions.

BACKGROUND

Therapeutic vascular occlusions (embolizations) are used to prevent ortreat pathological conditions in situ. Embolic coils can be used toocclude vessels in a variety of medical applications. Delivery ofembolic coils (e.g., through a catheter) can depend on the size and/orshape of the coils. Some embolic coils include fibers that can, forexample, enhance thrombosis at a treatment site.

SUMMARY

In one aspect, the invention features a wound ribbon in the shape of anembolic coil.

In another aspect, the invention features a method of making an emboliccoil that includes winding a ribbon into the shape of an embolic coil.

In an additional aspect, the invention features a medical deviceincluding a tubular body and at least one wound ribbon (e.g., aplurality of wound ribbons) that is in the shape of an embolic coil. Thetubular body has a lumen and the wound ribbon is disposed within thelumen.

In a further aspect, the invention features a method that includesadministering at least one wound ribbon (e.g., a plurality of woundribbons) to a subject. The wound ribbon is in the shape of an emboliccoil.

In another aspect, the invention features a method of using a medicaldevice that includes a tubular body and at least one wound ribbon thatis in the shape of an embolic coil. The tubular body has a lumen and thewound ribbon is disposed within the lumen. The method includes insertingthe tubular body into a lumen of a subject, and delivering the woundribbon into the lumen of the subject.

Embodiments can include one or more of the following features.

In some embodiments, the wound ribbon can include two ends, each ofwhich is not attached to a medical device (e.g., a catheter) or amedical device component (e.g., a guidewire). In certain embodiments,the embolic coil can include two ends, and the method may not includeattaching either of the ends to a medical device (e.g., a catheter) or amedical device component (e.g., a guidewire).

In some embodiments, the wound ribbon can include first and secondwindings. In certain embodiments, the first winding can contact thesecond winding. In some embodiments, the wound ribbon can include morethan two windings (e.g., at least five windings, at least ten windings,at least 15 windings, at least 20 windings, at least 50 windings, atleast 100 windings).

In certain embodiments, the ribbon can have a polygonal transversecross-section. For example, the ribbon can have a rectangular transversecross-section with a width and a length that is longer than the width.The length of the rectangular transverse cross-section can be at least0.001 inch (e.g., at least 0.0015 inch, at least 0.002 inch, at least0.003 inch, at least 0.004 inch, at least 0.005 inch) and/or at most0.006 inch (e.g., at most 0.005 inch, at most 0.004 inch, at most 0.003inch, at most 0.002 inch, at most 0.0015 inch). In some embodiments, thelength of the rectangular transverse cross-section can be 0.002 inch.The width of the rectangular transverse cross-section can be at least0.0005 inch (e.g., at least 0.001 inch, at least 0.0015 inch, at least0.002 inch, at least 0.003 inch, at least 0.004 inch, at least 0.0045inch) and/or at most 0.005 inch (e.g., at most 0.0045 inch, at most0.004 inch, at most 0.003 inch, at most 0.002 inch, at most 0.0015 inch,at most 0.001 inch). In certain embodiments, the width of therectangular transverse cross-section can be 0.001 inch. In someembodiments, the ratio of the length of the rectangular cross-section tothe width of the rectangular cross-section can be at least 1:1 (e.g., atleast about 1.25:1, at least about 2:1, at least about 5:1, at leastabout 10:1, at least about 20:1, at least about 30:1, at least about50:1) and/or at most about 75:1 (e.g., at most about 50:1, at most about30:1, at most about 20:1, at most about 10:1, at most about 5:1, at mostabout 2:1, at most about 1.25:1). In certain embodiments, the ratio ofthe length of the rectangular cross-section to the width of therectangular cross-section can be about 2:1. In some embodiments, theribbon can have a square transverse cross-section.

In certain embodiments, the wound ribbon can include at least one fiber(e.g., a plurality of fibers). In some embodiments, the wound ribbon caninclude two windings and at least one fiber that is disposed between thetwo windings. The fiber may include a polyester (e.g., polyethyleneterephthalate) and/or a polyamide (e.g., nylon).

In some embodiments, the wound ribbon can include a metal (e.g.,platinum), a metal alloy (e.g., stainless steel, Nitinol), and/or apolymer. In certain embodiments, the wound ribbon can include aradiopaque material. In some embodiments, the wound ribbon can include apolymer and a radiopaque material that is disposed in the polymer.

In certain embodiments, the embolic coil can have a primary shape withan outer diameter of at least 0.003 inch (e.g., at least 0.005 inch, atleast 0.01 inch, at least 0.012 inch, at least 0.015 inch, at least 0.02inch, at least 0.03 inch, at least 0.035 inch) and/or at most 0.038 inch(e.g., at most 0.035 inch, at most 0.03 inch, at most 0.02 inch, at most0.015 inch, at most 0.012 inch, at most 0.01 inch, at most 0.005 inch).In some embodiments, the embolic coil can have a primary shape with aninner diameter of at least 0.001 inch (e.g., at least 0.002 inch, atleast 0.004 inch, at least 0.005 inch, at least 0.01 inch, at least0.015 inch, at least 0.02 inch, at least 0.025 inch, at least 0.03 inch,at least 0.035 inch) and/or at most 0.036 inch (e.g., at most 0.035inch, at most 0.03 inch, at most 0.025 inch, at most 0.02 inch, at most0.015 inch, at most 0.01 inch, at most 0.005 inch, at most 0.004 inch,at most 0.002 inch).

In some embodiments, winding a ribbon into the shape of an embolic coilcan include forming first and second windings out of at least a portionof the ribbon. In certain embodiments, the first winding can contact thesecond winding. In some embodiments, the method can include disposing atleast one fiber between the first and second windings.

In certain embodiments, winding a ribbon into the shape of an emboliccoil can include winding the ribbon around a mandrel. The mandrel canhave an outer diameter of at least 0.001 inch (e.g., at least 0.004inch, at least 0.01 inch, at least 0.02 inch, at least 0.03 inch) and/orat most 0.033 inch (e.g., at most 0.03 inch, at most 0.02 inch, at most0.01 inch, at most 0.004 inch).

In some embodiments, the medical device can further include a pusherwire. The pusher wire can be disposed within the lumen of the tubularbody and/or can contact the wound ribbon.

In certain embodiments, the tubular body can be a catheter. In someembodiments, the tubular body can be an introducer sheath.

The method may be used to treat at least one of the followingconditions: aneurysms, arteriovenous malformations, traumatic fistulae,and tumors. In certain embodiments, the method can include embolizing alumen of a subject.

Embodiments can include one or more of the following advantages.

In some embodiments, an embolic coil can retain fibers relatively well(e.g., as the embolic coil is advanced and/or retracted during placementat a target site). For example, in certain embodiments, an embolic coilmay include windings that contact each other. This contact between thewindings can enhance the ability of the embolic coil to retain fibersthat are disposed between the windings. This can be advantageous, forexample, because it can reduce the likelihood of fibers dissociatingfrom the embolic coil (e.g., during delivery to a target site) andtraveling to a non-target site.

In certain embodiments, the structure of an embolic coil can be suchthat the embolic coil has a relatively high radiopacity. In someembodiments in which an embolic coil has a relatively high radiopacity,the embolic coil can exhibit enhanced visibility under X-ray fluoroscopy(e.g., when the embolic coil is in a subject). In certain embodiments,an embolic coil with a relatively high radiopacity can be viewed usingX-ray fluoroscopy (e.g., by a physician and/or a technician) withoutusing a radiopaque contrast agent. An embolic coil with a relativelyhigh radiopacity may be viewed using a non-invasive technique, and/ormay be monitored to determine the progress of a procedure and/or todetermine whether the embolic coil is migrating to a site that is nottargeted for treatment.

In some embodiments, an embolic coil that is formed of a wound ribbonmay be easier to maneuver (e.g., during delivery and/or at a targetsite) than an embolic coil of a comparable size that is not formed of awound ribbon. As an example, in certain embodiments, an embolic coilthat is formed of a wound ribbon can have a relatively high effectivecolumn strength, which can cause the embolic coil to have relativelygood pushability and to be relatively stable and easy to deliver to atarget site. As another example, in some embodiments, an embolic coilthat is formed of a wound ribbon can be relatively flexible. As anadditional example, in certain embodiments, an embolic coil that isformed of a wound ribbon can have relatively good secondary shaperetention. Thus, the embolic coil can, for example, assume its secondaryshape relatively easily after delivery to a target site. Themaneuverability of an embolic coil that is formed of a wound ribbon can,for example, allow the embolic coil to be relatively easily packed intoa target site, and/or can allow the embolic coil to conform relativelyeasily to the shape of the target site.

In certain embodiments, an embolic coil that is formed of a wound ribbonmay have a relatively smooth outer surface. The relatively smooth outersurface may enhance the deliverability of the embolic coil from adelivery device because, for example, there may be relatively littlefriction between the embolic coil and the walls of the delivery deviceif the embolic coil contacts the walls of the delivery device duringdelivery.

Other aspects, features, and advantages are in the description,drawings, and claims.

DESCRIPTION OF DRAWINGS

FIG. 1A is a perspective view of an embodiment of an embolic coil.

FIG. 1B is a side view of the embolic coil of FIG. 1A.

FIG. 1C is a side cross-sectional view of the embolic coil of FIG. 1A,taken along line IC-IC.

FIG. 1D is a cross-sectional view of the embolic coil of FIG. 1A, takenalong line ID-ID.

FIG. 2 is a side view of an embodiment of an embolic coil.

FIGS. 3A-3C illustrate the delivery of an embodiment of an embolic coilto the site of an aneurysm.

FIG. 4 is a perspective view of an embodiment of an embolic coil.

FIG. 5 is a perspective view of an embodiment of an embolic coil.

FIG. 6 is a perspective view of an embodiment of an embolic coil.

FIG. 7 is a perspective view of an embodiment of an embolic coil.

FIG. 8A is a front view of an embodiment of an embolic coil.

FIG. 8B is a side view of the embolic coil of FIG. 8A.

FIG. 9A is a front view of an embodiment of an embolic coil.

FIG. 9B is a side view of the embolic coil of FIG. 9A.

FIG. 10 is a side view of an embodiment of an embolic coil.

FIG. 11A is a side view of an embodiment of a process for forming anembolic coil.

FIG. 11B is an enlarged view of region 11B in FIG. 11A.

FIG. 12A is a side view of an embodiment of a mandrel.

FIGS. 12B and 12C are illustrations of an embodiment of a process forforming an embolic coil using the mandrel of FIG. 12A.

FIG. 13A is an illustration of an embodiment of a process for forming anembolic coil.

FIG. 13B is a side view of an embodiment of an embolic coil formed usingthe process of FIG. 13A.

FIG. 13C is a side cross-sectional view of the embolic coil of FIG. 13B,taken along line 13C-13C.

FIG. 14 is a side cross-sectional view of an embodiment of an emboliccoil.

FIG. 15 is a side cross-sectional view of an embodiment of an emboliccoil.

FIG. 16 is a side view of an embodiment of an embolic coil.

FIG. 17 is a side view of an embodiment of an embolic coil.

FIG. 18 illustrates the delivery of an embodiment of an embolic coilfrom an introducer sheath into a delivery device.

DETAILED DESCRIPTION

FIGS. 1A-1D show the primary shape of an embolic coil 10 that is formedof windings of a ribbon 18. Consecutive windings of ribbon 18, such aswindings 12 and 14, contact each other. As used herein, a ribbon refersto a strip of material having a non-circular transverse cross-section,such as a polygonal transverse cross-section (a transverse cross-sectionthat is a closed plane figure bounded by straight lines). As shown inFIG. 1C, ribbon 18 has a rectangular transverse cross-section with awidth W1 and a length L1 that is longer than width W1.

In some embodiments, length L1 can be at least 0.001 inch (e.g., atleast 0.0015 inch, at least 0.002 inch, at least 0.003 inch, at least0.004 inch, at least 0.005 inch) and/or at most 0.006 inch (e.g., atmost 0.005 inch, at most 0.004 inch, at most 0.003 inch, at most 0.002inch, at most 0.0015 inch). For example, length L1 may be 0.002 inch. Incertain embodiments, width W1 can be at least 0.0005 inch (e.g., atleast 0.001 inch, at least 0.0015 inch, at least 0.002 inch, at least0.003 inch, at least 0.004 inch, at least 0.0045 inch) and/or at most0.005 inch (e.g., at most 0.0045 inch, at most 0.004 inch, at most 0.003inch, at most 0.002 inch, at most 0.0015 inch, at most 0.001 inch). Forexample, width W1 may be 0.001 inch.

In some embodiments, as the ratio of length L1 to width W1 increases,the stability of embolic coil 10 can increase, and/or the likelihood ofembolic coil 10 retaining its shape (e.g., during delivery to a targetsite) can increase. In certain embodiments, as the ratio of length L1 towidth W1 decreases, the flexibility of embolic coil 10 can increase. Insome embodiments, the ratio of length L1 to width W1 can be selected sothat embolic coil 10 has good stability, shape retention, and/orflexibility. An embolic coil having one or more of these properties maybe relatively easy to deliver to, and/or pack into, a target site (e.g.,an aneurysmal sac).

In certain embodiments, the ratio of length L1 to width W1 can be atleast 1:1 (e.g., at least about 1.25:1, at least about 1.5:1, at leastabout 2:1, at least about 5:1, at least about 10:1, at least about 15:1,at least about 20:1, at least about 30:1, at least about 40:1, at leastabout 50:1, at least about 60:1, at least about 70:1), and/or at mostabout 75:1 (e.g., at most about 70:1, at most about 60:1, at most about50:1, at most about 40:1, at most about 30:1, at most about 20:1, atmost about 15:1, at most about 10:1, at most about 5:1, at most about2:1, at most about 1.5:1, at most about 1.25:1) For example, the ratioof length L1 to width W1 may be about 2:1.

As shown in FIG. 1A, ribbon 18 has a side 17 having a relatively smallthickness T1 and a side 19 having a relatively large thickness T2.Generally, thickness T1 can be equal to width W1, and thickness T2 canbe equal to length L1.

Typically, ribbon 18 can be formed of one or more materials that arecapable of being shaped into a coil form. For example, ribbon 18 may beformed of one or more materials that have sufficient flexibility and/ormalleability to be shaped into a coil form.

In some embodiments, ribbon 18 can be formed of one or more metals ormetal alloys, such as platinum, a platinum alloy (e.g.,platinum-tungsten alloy), stainless steel, Nitinol, or Elgiloy® alloy(from Elgiloy Specialty Materials). In certain embodiments, ribbon 18can be formed of one or more polymers. Examples of polymers includepolyolefins, polyurethanes, block copolymers, polyethers, andpolyimides. Other examples of polymers are disclosed, for example, inBuiser et al., U.S. patent application Ser. No. 11/311,617, filed onDec. 19, 2005, and entitled “Coils”, which is incorporated herein byreference. In some embodiments, ribbon 18 can be formed out of one ormore shape-memory materials, such as Nitinol and/or shape-memorypolymers. Examples of shape-memory polymers include shape-memorypolyurethanes and the Veriflex™ two-part thermoset shape-memory polymerresin system (from CRG Industries, Dayton, Ohio).

In some embodiments, it may be desirable to observe ribbon 18 usingX-ray fluoroscopy. In certain embodiments, ribbon 18 can include one ormore radiopaque materials that may enhance the visibility of ribbon 18under X-ray fluoroscopy. As an example, ribbon 18 may be formed of aradiopaque material. As another example, ribbon 18 may be formed of amaterial (e.g., a polymer) that encapsulates a radiopaque material,and/or may be formed of a material (e.g., a polymer) within which aradiopaque material is disposed. As an additional example, ribbon 18 mayinclude a coating of a radiopaque material.

As used herein, a radiopaque material refers to a material having adensity of about ten grams per cubic centimeter or greater (e.g., about25 grams per cubic centimeter or greater, about 50 grams per cubiccentimeter or greater). A radiopaque material can be, for example, ametal (e.g., tungsten, tantalum, platinum, palladium, lead, gold,titanium, silver), a metal alloy (e.g., stainless steel, an alloy oftungsten, an alloy of tantalum, an alloy of platinum, an alloy ofpalladium, an alloy of lead, an alloy of gold, an alloy of titanium, analloy of silver), a metal oxide (e.g., titanium dioxide, zirconiumoxide, aluminum oxide), bismuth subcarbonate, or barium sulfate. In someembodiments, a radiopaque material is a radiopaque contrast agent.Examples of radiopaque contrast agents include Omnipaque™, Renocal®,iodiamide meglumine, diatrizoate meglumine, ipodate calcium, ipodatesodium, iodamide sodium, iothalamate sodium, iopamidol, and metrizamide.Radiopaque contrast agents are commercially available from, for example,Bracco Diagnostic. Radiopaque materials are described, for example, inRioux et al., U.S. Patent Application Publication No. US 2004/0101564A1, published on May 27, 2004, which is incorporated herein byreference.

In some embodiments, an embolic coil that is formed of a wound ribbon,such as embolic coil 10, can have a relatively high density ofradiopaque material (e.g., relative to conventional embolic coils). Thiscan cause the embolic coil to have a relatively high radiopacity, whichcan be advantageous because as the radiopacity of an embolic coilincreases, the visibility of the embolic coil under X-ray fluoroscopycan also increase.

As shown in FIGS. 1C and 1D, embolic coil 10 in its primary shape has aninner diameter ID1 and an outer diameter OD1. In some embodiments, innerdiameter ID1 is at least 0.001 inch (e.g., at least 0.002 inch, at least0.004 inch, at least 0.005 inch, at least 0.01 inch, at least 0.015inch, at least 0.02 inch, at least 0.025 inch, at least 0.03 inch, atleast 0.035 inch) and/or at most 0.036 inch (e.g., at most 0.035 inch,at most 0.03 inch, at most 0.025 inch, at most 0.02 inch, at most 0.015inch, at most 0.01 inch, at most 0.005 inch, at most 0.004 inch, at most0.002 inch). In certain embodiments, outer diameter OD1 is at least0.003 inch (e.g., at least 0.005 inch, at least 0.01 inch, at least0.012 inch, at least 0.015 inch, at least 0.02 inch, at least 0.03 inch,at least 0.035 inch) and/or at most 0.038 inch (e.g., at most 0.035inch, at most 0.03 inch, at most 0.02 inch, at most 0.015 inch, at most0.012 inch, at most 0.01 inch, at most 0.005 inch).

As shown in FIG. 1C, embolic coil 10 in its primary shape has a lengthL2. In some embodiments, length L2 can be at least about 0.2 centimeter(e.g., at least about 0.5 centimeter, at least about one centimeter, atleast about five centimeters, at least about 10 centimeters, at leastabout 15 centimeters, at least about 20 centimeters, at least about 30centimeters), and/or at most about 40 centimeters (e.g., at most about30 centimeters, at most about 20 centimeters, at most about 15centimeters, at most about 10 centimeters, at most about fivecentimeters, at most about one centimeter, at most about 0.5centimeter).

The pitch of an embolic coil is the sum of the thickness of one windingof ribbon (e.g., winding 12 of ribbon 18) and the amount of spacebetween that winding and a consecutive winding of ribbon (e.g., winding14 of ribbon 18). FIG. B shows the pitch P1 of embolic coil 10. Becausethe windings of embolic coil 10 are flush with each other, pitch P1 ofembolic coil 10 is equal to the thickness of a winding of embolic coil10, such as thickness T3 of winding 12 (FIG. 1A). The thickness of awinding of embolic coil 10 is, in turn, equal to width W1 of therectangular transverse cross-section of ribbon 18. In some embodiments,pitch P1 can be at most 0.005 inch (e.g., at most 0.0045 inch, at most0.004 inch, at most 0.003 inch, at most 0.002 inch, at most 0.0015 inch,at most 0.001 inch), and/or at least 0.0005 inch (e.g., at least 0.001inch, at least 0.0015 inch, at least 0.002 inch, at least 0.003 inch, atleast 0.004 inch, at least 0.0045 inch).

In certain embodiments, embolic coil 10 can further include fibers. Forexample, FIG. 2 shows embolic coil 10 with fibers 22 tightly fittedbetween consecutive windings, such as windings 12 and 14. Thesubstantial contact between consecutive windings of ribbon 18 mayenhance the ability of embolic coil 10 to retain fibers 22. In someembodiments, the distance D between the location of one bunch of fibers22 and the location of the next bunch of fibers 22 on embolic coil 10can be at least about two millimeters (e.g., at least about fourmillimeters, at least about six millimeters, at least about eightmillimeters), and/or at most about nine millimeters (e.g., at most abouteight millimeters, at most about six millimeters, at most about fourmillimeters). While FIG. 2 shows bunches of fibers that are allseparated from their neighboring bunches of fibers by the same number ofwindings, in some embodiments, an embolic coil may have a differentconfiguration of fibers. For example, in certain embodiments, an emboliccoil may have only one bunch of fibers, or may have bunches of fibersthat are separated from their neighboring bunches of fibers by differentnumbers of windings. As an example, one bunch of fibers on an emboliccoil may be separated from a neighboring bunch of fibers by threewindings, while another bunch of fibers on the embolic coil is separatedfrom a neighboring bunch of fibers by five windings.

Fibers 22 typically can be made of one or more materials that canenhance thrombosis (e.g., at a target site). In some embodiments, fibers22 can be made of one or more polyesters and/or polyamides. Examples ofmaterials from which fibers 22 can be made include polyethyleneterephthalate (e.g., Dacron®), nylon, and collagen. In certainembodiments, fibers 24 can have a length of from about 0.5 millimeter toabout five millimeters (e.g., about 2.5 millimeters).

Embolic coils can generally be used in a number of differentapplications, such as neurological applications and/or peripheralapplications. In some embodiments, embolic coils can be used to embolizea lumen of a subject (e.g., to occlude a vessel), and/or to treat ananeurysm (e.g., an intercranial aneurysm), an arteriovenous malformation(AVM), or a traumatic fistula. In certain embodiments, embolic coils canbe used to embolize a tumor (e.g., a liver tumor). In some embodiments,embolic coils can be used in transarterial chemoembolization (TACE).

FIGS. 3A-3C show the use of embolic coil 10 to fill and occlude ananeurysmal sac. FIG. 3A shows embolic coil 10, loaded into a lumen 52 ofa catheter 50, and a pusher wire 60 disposed outside of catheter 50. Insome embodiments in which embolic coil 10 has an outer diameter OD1 of0.018 inch, catheter 50 can have an inner diameter of 0.021 inch. Anexample of a catheter having an inner diameter of 0.021 inch is theRenegade® 18 Microcatheter (from Boston Scientific Corp.).

As shown in FIG. 3A, embolic coil 10 includes a proximal end 11 and adistal end 13. Neither proximal end 11 nor distal end 13 is attached toanything. For example, neither proximal end 11 nor distal end 13 isattached to a medical device (e.g., a catheter) or a medical devicecomponent (e.g., a guidewire). In some embodiments, embolic coil 10 canbe disposed within a carrier fluid (e.g., a saline solution, a contrastagent, a heparin solution) while embolic coil 10 is within lumen 52 ofcatheter 50. In FIG. 3B, catheter 50 is delivered into a lumen 62 of asubject, and pusher wire 60 is inserted into lumen 52 of catheter 50,such that pusher wire 60 contacts embolic coil 10. Pusher wire 60 isthen used to push embolic coil 10 out of catheter 50, into lumen 62, andtoward an aneurysmal sac 64 formed in a wall 66 of lumen 62. FIG. 3Cshows embolic coil 10 filling aneurysmal sac 64 after embolic coil 10has been pushed out of catheter 50 by pusher wire 60. By fillinganeurysmal sac 64, embolic coil 10 helps to occlude aneurysmal sac 64.In some embodiments in which embolic coil 10 includes fibers (e.g.,fibers 22), this occlusion of aneurysmal sac 64 can be accelerated bythe fibers, which can enhance thrombosis within aneurysmal sac 64. Anaccelerated embolization procedure can benefit the subject by, forexample, reducing exposure time to fluoroscopy.

Generally, the design of embolic coil 10 (e.g., the substantial contactbetween consecutive windings of ribbon 18) can result in embolic coil 10having a relatively high effective column strength. The effective columnstrength of embolic coil 10 is the column strength (the compression loadat which embolic coil 10 will buckle) of embolic coil 10 when emboliccoil 10 is constrained within lumen 52 of catheter 50. Because emboliccoil 10 can have a relatively high effective column strength, emboliccoil 10 can also have good pushability. As a result, in some embodimentsin which embolic coil 10 includes fibers 22, even if fibers 22 adhere tothe walls of lumen 52, embolic coil 10 can be sufficiently pushable toovercome the adhesion.

In general, embolic coil 10 has a primary shape and a secondary shape.Embolic coil 10 exhibits only its primary shape when embolic coil 10 isextended within lumen 52 of catheter 50 (as shown in FIG. 3A). Asembolic coil 10 exits catheter 50, however, embolic coil 10 furtherassumes its secondary shape, which allows embolic coil 10 to fillaneurysmal sac 64. Typically, the primary shape of embolic coil 10 canbe selected for deliverability, and the secondary shape of embolic coil10 can be selected for application (e.g., embolization of an aneurysm).

As FIGS. 4-10 illustrate, an embolic coil can have any of a number ofdifferent secondary shapes, which can depend on the particularapplication for the embolic coil.

For example, FIG. 4 shows an embolic coil 100 with a spiral secondaryshape, which can be used, for example, to provide a supportive frameworkalong a vessel wall. Alternatively or additionally, an embolic coil witha spiral secondary shape can be used to hold other embolic coils thatare subsequently delivered to the target site.

FIG. 5 shows an embolic coil 110 with a single apex vortex secondaryshape, which can be used, for example, to close the center of a targetsite (e.g., a vessel, an aneurysm) that is to be occluded, and/or toocclude a target site in conjunction with an embolic coil such asembolic coil 100 (FIG. 4). An embolic coil with a single apex vortexsecondary shape can be used to occlude a vessel having low flow,intermediate flow, or high flow. In some embodiments, multiple emboliccoils with single apex vortex secondary shapes can be used to occlude avessel. In certain embodiments, an embolic coil with a single apexvortex secondary shape can be used as a packing coil, such that the coilcan be packed into a vessel that is slightly smaller than the diameterof the coil. As an example, a six-millimeter diameter coil can be packedinto a vessel having a five-millimeter diameter. In some embodiments, anembolic coil with a single apex vortex secondary shape can be used toembolize a tumor and/or to treat gastrointestinal bleeding.

As shown in FIG. 6, an embolic coil 120 can have a dual apex vortexsecondary shape (also known as a diamond secondary shape), which, likethe single apex vortex secondary shape, can used, for example, to closethe center of a target site (e.g., a vessel, an aneurysm) that is to beoccluded, and/or to occlude a target site in conjunction with an emboliccoil such as embolic coil 100 (FIG. 4). An embolic coil with a dual apexvortex secondary shape can be used to occlude a vessel having low flow,intermediate flow, or high flow, and can be used alone or in combinationwith other embolic coils (e.g., other embolic coils having dual apexvortex secondary shapes). In certain embodiments, an embolic coil with adual apex vortex secondary shape can be used as a packing coil. In someembodiments, an embolic coil with a dual apex vortex secondary shape canbe used to embolize a tumor and/or to treat gastrointestinal bleeding.

FIG. 7 shows an embolic coil 130 with a secondary shape in the form of aJ, which can be used, for example, to fill remaining space in ananeurysm that was not filled by other coils. In some embodiments, anoperator (e.g., a physician) can hook the curved portion of embolic coil130 into a coil or coil mass that has already been deployed at a targetsite, and then shape the straighter portion of coil 130 to fill thetarget site.

FIGS. 8A and 8B show an embolic coil 140 having a complex helicalsecondary shape. An embolic coil with a complex helical secondary shapecan be used, for example, to frame a target site. In certainembodiments, an embolic coil with a complex helical secondary shape canbe used as an anchoring coil that helps to hold other embolic coils inplace at a target site (e.g., thereby allowing additional embolic coilsto be packed into the target site).

FIGS. 9A and 9B show an embolic coil 150 having a helical secondaryshape. An embolic coil with a helical secondary shape can be used, forexample, as a packing coil.

FIG. 10 shows an embolic coil 160 having a straight secondary shape. Anembolic coil with a straight secondary shape can be used, for example,in a relatively small vessel (e.g., to block blood flow to a tumor).

In some embodiments, an embolic coil (e.g., embolic coil 10) can berelatively flexible. For example, in certain embodiments, the stiffnessof an embolic coil can be at most about 0.01 pound-force (e.g., at mostabout 0.004 pound-force), and/or at least about 0.001 pound-force (e.g.,at least about 0.004 pound-force). Coil stiffness is determined bymeasuring the force required to compress the largest outer diameter of asecondary shape of a coil by five percent. A dynamic testing machine isused to measure coil stiffness as follows. The region of a secondarycoil having the largest outer diameter is cut away from the secondarycoil and placed in the gripping mechanism of the testing machine, suchthat only half of the largest outer diameter of the secondary coil (asemi-circle shape) is exposed. The sample is placed directly below ananvil-like fixture that compresses down on the surface of the outerdiameter. The force required to compress the sample by five percent ofthe largest outer diameter of the secondary shape of the coil is thenmeasured.

FIGS. 11A and 11B illustrate a process for forming an embolic coil(e.g., embolic coil 10) in its primary shape, and FIGS. 12A-12C show aprocess for forming the secondary shape of the embolic coil.

As shown in FIG. 11A, a coil-forming apparatus 200 includes a mandrel210 held by two rotatable chucks 220 and 230. A spool 240 of ribbon 250is disposed above mandrel 210, and is attached to a linear drive 260. Toform an embolic coil in its primary shape, chucks 220 and 230 areactivated so that they rotate in the direction of arrows A2 and A3,thereby rotating mandrel 210. Linear drive 260 also is activated, andmoves spool 240 in the direction of arrow A1. The rotation of mandrel210 pulls ribbon 250 from spool 240 at a predetermined pull-off angle,and causes ribbon 250 to wrap around mandrel 210, forming a coil 270.

As shown in FIG. 11B, ribbon 250 has a side 252 having a relativelysmall thickness T4 and a side 254 having a relatively large thicknessT5. In forming coil 270, ribbon 250 is wound around mandrel 210 on edge,so that the thickness T6 of each winding (e.g., winding 272) of coil 270is equal to thickness T4 of side 252. The winding of ribbon 250 on edgeto form coil 270 can cause the windings of coil 270 to have a relativelyhigh degree of contact with each other.

As FIG. 11A shows, the pull-off angle (α) is the angle between axis PA1,which is perpendicular to longitudinal axis LA1 of mandrel 210, and theportion 280 of ribbon 250 between spool 240 and coil 270. In someembodiments, a can be from about one degree to about six degrees (e.g.,from about 1.5 degrees to about five degrees, from about 1.5 degrees toabout 2.5 degrees, about two degrees). In certain embodiments, acontroller (e.g., a programmable logic controller) can be used tomaintain the pull-off angle in coil-forming apparatus 200. Becausemandrel 210 is rotating as it is pulling ribbon 250 from spool 240, andbecause linear drive 260 is moving spool 240 in the direction of arrowA1, ribbon 250 forms coil 270 in a primary shape around mandrel 210.Coil 270 can be formed, for example, at room temperature (25° C.).

After coil 270 has been formed, chucks 220 and 230, and linear drive260, are deactivated, and portion 280 of ribbon 250 is cut. Mandrel 210is then released from chuck 220, and coil 270 is pulled off of mandrel210. While coil 270 might lose some of its primary shape as it is pulledoff of mandrel 210, coil 270 can generally return to its primary shapeshortly thereafter, because of memory imparted to coil 270 duringformation. In some embodiments, after coil 270 has been removed frommandrel 210, one or both of the ends of coil 270 can be heated andmelted to form rounder, more biocompatible (e.g., atraumatic) ends.

Mandrel 210 can be formed of, for example, a metal or a metal alloy,such as stainless steel. In some embodiments, mandrel 210 can be formedof one or more polymers, such as Teflon® (polytetrafluoroethylene) orDelrin® (polyoxymethylene). In certain embodiments, mandrel 210 can beformed of a shape-memory material, such as Nitinol.

Mandrel 210 has an outer diameter OD2 (FIG. 1B). In some embodiments,outer diameter OD2 can be at least 0.0005 inch (e.g., at least 0.001inch, at least 0.004 inch, at least 0.005 inch, at least 0.01 inch, atleast 0.015 inch, at least 0.02 inch, at least 0.025 inch) and/or atmost 0.03 inch (e.g., at most 0.025 inch, at most 0.02 inch, at most0.015 inch, at most 0.01 inch, at most 0.005 inch, at most 0.004 inch,at most 0.001 inch).

The tension of mandrel 210 as it is held between chucks 220 and 230preferably is sufficiently high to avoid vibration of mandrel 210 duringthe winding process, and sufficiently low to avoid stretching of mandrel210 during the winding process. In some instances, significantstretching of mandrel 210 during the winding process could cause coil270 to have a smaller primary shape than desired, and/or could make itrelatively difficult to remove coil 270 from mandrel 210. In certainembodiments, the tension of mandrel 210 can be from about 100 grams toabout 1,000 grams (e.g., from about 300 grams to about 600 grams, fromabout 400 grams to about 500 grams). For example, the tension of mandrel210 can be about 506 grams.

In some embodiments, ribbon 250 can be wound around mandrel 210 at atension of at least about four grams (e.g., at least about five grams,at least about six grams, at least about 10 grams, at least about 22grams, at least about 27 grams, at least about 32 grams, at least about40 grams, at least about 60 grams, at least about 65 grams, at leastabout 85 grams) and/or at most about 100 grams (e.g., at most about 85grams, at most about 65 grams, at most about 60 grams, at most about 40grams, at most about 32 grams, at most about 27 grams, at most about 22grams, at most about 10 grams, at most about six grams, at most aboutfive grams).

In certain embodiments, the length of coil 270 in its primary shape andwhile under tension on mandrel 210 can be from about 10 centimeters toabout 250 centimeters (e.g., from about 50 centimeters to about 200centimeters, from about 130 centimeters to about 170 centimeters, fromabout 144 centimeters to about 153 centimeters, from about 147centimeters to about 153 centimeters). For example, the length of coil270 in its primary shape and while under tension on mandrel 210 can beabout 132 centimeters or about 147 centimeters. Coil 270 may recoil tosome extent (e.g., by at most about five centimeters) when portion 280of ribbon 250 is severed, such that coil 270 will be somewhat smalleronce it has been removed from mandrel 210. In some embodiments, coil 270can have a length of from about five centimeters to about 225centimeters (e.g., from about 25 centimeters to about 170 centimeters,from about 120 centimeters to about 140 centimeters, from about 137centimeters to about 140 centimeters) after being removed from mandrel210. After coil 270 has been removed from mandrel 210, coil 270 can becut into smaller coils.

Once coil 270 has been formed in its primary shape, coil 270 can befurther shaped into a secondary shape, as shown in FIGS. 12A-12C.

FIG. 12A shows a mandrel 310 used to form the secondary shape of coil270. While mandrel 310 is shaped to form a diamond, other types ofmandrels can be used to form other secondary shapes. Mandrel 310 isformed of a diamond-shaped block 320 with grooves 330 cut into itssurface. As shown in FIGS. 12B and 12C, coil 270 in its primary shape iswrapped around mandrel 310, such that coil 270 fills grooves 330,creating the secondary shape. The ends of coil 270 are then attached(e.g., pinned) to mandrel 310, and coil 270 is heat-treated to impartmemory to coil 270. In some embodiments, coil 270 can be heat-treated ata temperature of at least about 1000° C. (e.g., at least about 1050° C.,at least about 1100° C., at least about 1150° C.), and/or at most about1200° C. (e.g., at most about 1150° C., at most about 1100° C., at mostabout 1050° C.). In certain embodiments, the heat treatment of coil 270can last for a period of from about 10 minutes to about 40 minutes(e.g., about 25 minutes). After being heat-treated, coil 270 isunwrapped from mandrel 310. The removal of coil 270 from mandrel 310allows coil 270 to reassume its secondary shape. In some embodiments,after coil 270 has been removed from mandrel 310, one or both of theends of coil 270 can be heated and melted to form rounder, morebiocompatible (e.g., atraumatic) ends.

Mandrel 310 can be formed of, for example, a metal or a metal alloy(e.g., stainless steel). In some embodiments, mandrel 310 can be formedof a plated metal or a plated metal alloy (e.g., chrome-plated stainlesssteel).

After coil 270 has been removed from mandrel 310, fibers can be attachedto coil 270. In some embodiments, coil 270 can be stretched prior toattaching the fibers, so that coil 270 is in its extended primary shape,and can then be loaded onto a fibering mandrel (e.g., a fibering mandrelfrom Sematool Mold and Die Co., Santa Clara, Calif.). In certainembodiments, fibers can be snapped in between windings of coil 270. Insome embodiments, fibers can be tied to windings of coil 270 and/orwrapped around windings of coil 270. In certain embodiments, fibers canbe bonded (e.g., adhesive bonded) to ribbon 250 of coil 270. In certainembodiments, one portion (e.g., one end) of a bunch of fibers can besnapped in between windings in one region of coil 270, and anotherportion (e.g., the other end) of the same bunch of fibers can be wrappedaround part of coil 270 and snapped in between windings in anotherregion of coil 270.

Embolic coils and methods of making embolic coils are described, forexample, in Elliott et al., U.S. patent application Ser. No. 11/000,741,filed on Dec. 1, 2004, and entitled “Embolic Coils”, which isincorporated herein by reference.

In some embodiments, an embolic coil such as embolic coil 10 can includeone or more therapeutic agents (e.g., drugs). For example, ribbon 18and/or fibers 22 can include one or more therapeutic agents (e.g.,dispersed within and/or encapsulated by the material of ribbon 18 and/orfibers 22), and/or can be coated with one or more coatings including oneor more therapeutic agents. In some embodiments, the therapeutic agentscan be dispersed within, and/or encapsulated by, the coatings. Emboliccoil 10 can, for example, be used to deliver the therapeutic agents to atarget site.

In certain embodiments, one component of embolic coil 10 (e.g., acoating on ribbon 18) can include one or more therapeutic agents thatare the same as, or different from, one or more therapeutic agents inanother component of embolic coil 10 (e.g., a coating on fibers 22). Incertain embodiments in which ribbon 18 and/or fibers 22 are coated bycoatings including one or more therapeutic agents, the coatings caninclude one or more bioerodible and/or bioabsorbable materials. When thecoatings are eroded and/or absorbed, they can release the therapeuticagents into the body of the subject (e.g., during delivery and/or at atarget site).

In some embodiments, embolic coil 10 can include one or more therapeuticagents that are coated onto ribbon 18, fibers 22, and/or one or morecoatings on ribbon 18 and/or fibers 22. In certain embodiments, atherapeutic agent can be compounded with a polymer that is included in acoating on ribbon 18 and/or fibers 22. In some embodiments, atherapeutic agent can be applied to the surface of embolic coil 10 byexposing embolic coil 10 to a high concentration solution of thetherapeutic agent.

In some embodiments, a therapeutic agent-coated embolic coil can includea coating (e.g., a bioerodible and/or bioabsorbable polymer coating)over the surface of the therapeutic agent. The coating can assist incontrolling the rate at which therapeutic agent is released from theembolic coil. For example, the coating can be in the form of a porousmembrane. The coating can delay an initial burst of therapeutic agentrelease. The coating can be applied by dipping or spraying the emboliccoil. The coating can include therapeutic agent or can be substantiallyfree of therapeutic agent. The therapeutic agent in the coating can bethe same as or different from a therapeutic agent on a surface layer ofthe embolic coil and/or within the embolic coil (e.g., within a ribbonforming the embolic coil). A polymer coating (e.g., that is bioerodibleand/or bioabsorbable) can be applied to an embolic coil surface and/orto a coated embolic coil surface in embodiments in which a highconcentration of therapeutic agent has not been applied to the emboliccoil surface or to the coated embolic coil surface.

Coatings are described, for example, in Buiser et al., U.S. patentapplication Ser. No. 11/311,617, filed on Dec. 19, 2005, and entitled“Coils”, and in DiMatteo et al., U.S. Patent Application Publication No.US 2004/0076582 A1, published on Apr. 22, 2004, and entitled “AgentDelivery Particle”, both of which are incorporated herein by reference.

In some embodiments, one or more embolic coils can be disposed in atherapeutic agent that can serve as a pharmaceutically acceptablecarrier.

Therapeutic agents include genetic therapeutic agents, non-genetictherapeutic agents, and cells, and can be negatively charged, positivelycharged, amphoteric, or neutral. Therapeutic agents can be, for example,materials that are biologically active to treat physiologicalconditions; pharmaceutically active compounds; gene therapies; nucleicacids with and without carrier vectors (e.g., recombinant nucleic acids,DNA (e.g., naked DNA), cDNA, RNA, genomic DNA, cDNA or RNA in anon-infectious vector or in a viral vector which may have attachedpeptide targeting sequences, antisense nucleic acids (RNA, DNA));peptides (e.g., growth factor peptides, such as basic fibroblast growthfactor (bFGF)); oligonucleotides; gene/vector systems (e.g., anythingthat allows for the uptake and expression of nucleic acids); DNAchimeras (e.g., DNA chimeras which include gene sequences and encodingfor ferry proteins such as membrane translocating sequences (“MTS”) andherpes simplex virus-1 (“VP22”)); compacting agents (e.g., DNAcompacting agents); viruses; polymers; hyaluronic acid; proteins (e.g.,enzymes such as ribozymes, asparaginase); immunologic species;nonsteroidal anti-inflammatory medications; chemoagents; pain managementtherapeutics; oral contraceptives; progestins; gonadotrophin-releasinghormone agonists; chemotherapeutic agents; and radioactive species(e.g., radioisotopes, radioactive molecules). Non-limiting examples oftherapeutic agents include anti-thrombogenic agents; antioxidants;angiogenic and anti-angiogenic agents and factors; anti-proliferativeagents (e.g., agents capable of blocking smooth muscle cellproliferation); calcium entry blockers; and survival genes which protectagainst cell death (e.g., anti-apoptotic Bcl-2 family factors and Aktkinase).

Exemplary non-genetic therapeutic agents include: anti-thrombotic agentssuch as heparin, heparin derivatives, urokinase, and PPack(dextrophenylalanine proline arginine chloromethylketone);anti-inflammatory agents such as dexamethasone, prednisolone,corticosterone, budesonide, estrogen, acetyl salicylic acid,sulfasalazine and mesalamine;antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel,5-fluorouracil, cisplatin, methotrexate, doxorubicin, vinblastine,vincristine, epothilones, endostatin, angiostatin, angiopeptin,monoclonal antibodies capable of blocking smooth muscle cellproliferation, and thymidine kinase inhibitors; anesthetic agents suchas lidocaine, bupivacaine and ropivacaine; anti-coagulants such asD-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound,heparin, hirudin, antithrombin compounds, platelet receptor antagonists,anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin,prostaglandin inhibitors, platelet inhibitors and tick antiplateletfactors or peptides; vascular cell growth promoters such as growthfactors, transcriptional activators, and translational promoters;vascular cell growth inhibitors such as growth factor inhibitors (e.g.,PDGF inhibitor-Trapidil), growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; protein kinase and tyrosine kinase inhibitors (e.g.,tyrphostins, genistein, quinoxalines); prostacyclin analogs;cholesterol-lowering agents; angiopoietins; antimicrobial agents such astriclosan, cephalosporins, aminoglycosides and nitrofurantoin; cytotoxicagents, cytostatic agents and cell proliferation affectors; vasodilatingagents; and agents that interfere with endogenous vasoactive mechanisms.

Exemplary genetic therapeutic agents include: anti-sense DNA and RNA;DNA coding for anti-sense RNA, tRNA or rRNA to replace defective ordeficient endogenous molecules, angiogenic factors including growthfactors such as acidic and basic fibroblast growth factors, vascularendothelial growth factor, epidermal growth factor, transforming growthfactor α and β, platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor a, hepatocytegrowth factor, and insulin like growth factor, cell cycle inhibitorsincluding CD inhibitors, thymidine kinase (“TK”) and other agents usefulfor interfering with cell proliferation, and the family of bonemorphogenic proteins (“BMP's”), including BMP2, BMP3, BMP4, BMP5, BMP6(Vgr1), BMP7 (OP1), BMP8, BMP9, BMP10, BM11, BMP12, BMP13, BMP14, BMP15,and BMP16. Currently preferred BMP's are any of BMP2, BMP3, BMP4, BMP5,BMP6 and BMP7. These dimeric proteins can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively or additionally, molecules capable of inducingan upstream or downstream effect of a BMP can be provided. Suchmolecules include any of the “hedgehog” proteins, or the DNA's encodingthem. Vectors of interest for delivery of genetic therapeutic agentsinclude: plasmids; viral vectors such as adenovirus (AV),adenoassociated virus (AAV) and lentivirus; and non-viral vectors suchas lipids, liposomes and cationic lipids.

Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

Several of the above and numerous additional therapeutic agentsappropriate for the practice of the present invention are disclosed inKunz et al., U.S. Pat. No. 5,733,925, assigned to NeoRx Corporation,which is incorporated herein by reference. Therapeutic agents disclosedin this patent include the following:

“Cytostatic agents” (i.e., agents that prevent or delay cell division inproliferating cells, for example, by inhibiting replication of DNA or byinhibiting spindle fiber formation). Representative examples ofcytostatic agents include modified toxins, methotrexate, adriamycin,radionuclides (e.g., such as disclosed in Fritzberg et al., U.S. Pat.No. 4,897,255), protein kinase inhibitors, including staurosporin, aprotein kinase C inhibitor of the following formula:

as well as diindoloalkaloids having one of the following generalstructures:

as well as stimulators of the production or activation of TGF-beta,including Tamoxifen and derivatives of functional equivalents (e.g.,plasmin, heparin, compounds capable of reducing the level orinactivating the lipoprotein Lp(a) or the glycoproteinapolipoprotein(a)) thereof, TGF-beta or functional equivalents,derivatives or analogs thereof, suramin, nitric oxide releasingcompounds (e.g., nitroglycerin) or analogs or functional equivalentsthereof, paclitaxel or analogs thereof (e.g., taxotere), inhibitors ofspecific enzymes (such as the nuclear enzyme DNA topoisomerase II andDNA polymerase, RNA polymerase, adenyl guanyl cyclase), superoxidedismutase inhibitors, terminal deoxynucleotidyl-transferase, reversetranscriptase, antisense oligonucleotides that suppress smooth musclecell proliferation and the like. Other examples of “cytostatic agents”include peptidic or mimetic inhibitors (i.e., antagonists, agonists, orcompetitive or non-competitive inhibitors) of cellular factors that may(e.g., in the presence of extracellular matrix) trigger proliferation ofsmooth muscle cells or pericytes: e.g., cytokines (e.g., interleukinssuch as IL-1), growth factors (e.g., PDGF, TGF-alpha or -beta, tumornecrosis factor, smooth muscle- and endothelial-derived growth factors,i.e., endothelin, FGF), homing receptors (e.g., for platelets orleukocytes), and extracellular matrix receptors (e.g., integrins).Representative examples of useful therapeutic agents in this category ofcytostatic agents addressing smooth muscle proliferation include:subfragments of heparin, triazolopyrimidine (trapidil; a PDGFantagonist), lovastatin, and prostaglandins E1 or 12.

Agents that inhibit the intracellular increase in cell volume (i.e., thetissue volume occupied by a cell), such as cytoskeletal inhibitors ormetabolic inhibitors. Representative examples of cytoskeletal inhibitorsinclude colchicine, vinblastin, cytochalasins, paclitaxel and the like,which act on microtubule and microfilament networks within a cell.Representative examples of metabolic inhibitors include staurosporin,trichothecenes, and modified diphtheria and ricin toxins, Pseudomonasexotoxin and the like. Trichothecenes include simple trichothecenes(i.e., those that have only a central sesquiterpenoid structure) andmacrocyclic trichothecenes (i.e., those that have an additionalmacrocyclic ring), e.g., a verrucarins or roridins, including VerrucarinA, Verrucarin B, Verrucarin J (Satratoxin C), Roridin A, Roridin C,Roridin D, Roridin E (Satratoxin D), Roridin H.

Agents acting as an inhibitor that blocks cellular protein synthesisand/or secretion or organization of extracellular matrix (i.e., an“anti-matrix agent”). Representative examples of “anti-matrix agents”include inhibitors (i.e., agonists and antagonists and competitive andnon-competitive inhibitors) of matrix synthesis, secretion and assembly,organizational cross-linking (e.g., transglutaminases cross-linkingcollagen), and matrix remodeling (e.g., following wound healing). Arepresentative example of a useful therapeutic agent in this category ofanti-matrix agents is colchicine, an inhibitor of secretion ofextracellular matrix. Another example is tamoxifen for which evidenceexists regarding its capability to organize and/or stabilize as well asdiminish smooth muscle cell proliferation following angioplasty. Theorganization or stabilization may stem from the blockage of vascularsmooth muscle cell maturation in to a pathologically proliferating form.

Agents that are cytotoxic to cells, particularly cancer cells. Preferredagents are Roridin A, Pseudomonas exotoxin and the like or analogs orfunctional equivalents thereof. A plethora of such therapeutic agents,including radioisotopes and the like, have been identified and are knownin the art. In addition, protocols for the identification of cytotoxicmoieties are known and employed routinely in the art.

A number of the above therapeutic agents and several others have alsobeen identified as candidates for vascular treatment regimens, forexample, as agents targeting restenosis. Such agents include one or moreof the following: calcium-channel blockers, including benzothiazapines(e.g., diltiazem, clentiazem); dihydropyridines (e.g., nifedipine,amlodipine, nicardapine); phenylalkylamines (e.g., verapamil); serotoninpathway modulators, including 5-HT antagonists (e.g., ketanserin,naftidrofuryl) and 5-HT uptake inhibitors (e.g., fluoxetine); cyclicnucleotide pathway agents, including phosphodiesterase inhibitors (e.g.,cilostazole, dipyridamole), adenylate/guanylate cyclase stimulants(e.g., forskolin), and adenosine analogs; catecholamine modulators,including aantagonists (e.g., prazosin, bunazosine), β-antagonists(e.g., propranolol), and α/β-antagonists (e.g., labetalol, carvedilol);endothelin receptor antagonists; nitric oxide donors/releasingmolecules, including organic nitrates/nitrites (e.g., nitroglycerin,isosorbide dinitrate, amyl nitrite), inorganic nitroso compounds (e.g.,sodium nitroprusside), sydnonimines (e.g., molsidomine, linsidomine),nonoates (e.g., diazenium diolates, NO adducts of alkanediamines),S-nitroso compounds, including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers),C-nitroso-, O-nitroso- and N-nitroso-compounds, and L-arginine; ACEinhibitors (e.g., cilazapril, fosinopril, enalapril); ATII-receptorantagonists (e.g., saralasin, losartin); platelet adhesion inhibitors(e.g., albumin, polyethylene oxide); platelet aggregation inhibitors,including aspirin and thienopyridine (ticlopidine, clopidogrel) and GPIb/IIIa inhibitors (e.g., abciximab, epitifibatide, tirofiban,intergrilin); coagulation pathway modulators, including heparinoids(e.g., heparin, low molecular weight heparin, dextran sulfate,β-cyclodextrin tetradecasulfate), thrombin inhibitors (e.g., hirudin,hirulog, PPACK (D-phe-L-propyl-L-arg-chloromethylketone), argatroban),FXa inhibitors (e.g., antistatin, TAP (tick anticoagulant peptide)),vitamin K inhibitors (e.g., warfarin), and activated protein C;cyclooxygenase pathway inhibitors (e.g., aspirin, ibuprofen,flurbiprofen, indomethacin, sulfinpyrazone); natural and syntheticcorticosteroids (e.g., dexamethasone, prednisolone, methprednisolone,hydrocortisone); lipoxygenase pathway inhibitors (e.g.,nordihydroguairetic acid, caffeic acid; leukotriene receptorantagonists; antagonists of E- and P-selectins; inhibitors of VCAM-1 andICAM-1 interactions; prostaglandins and analogs thereof, includingprostaglandins such as PGE1 and PGI2; prostacyclin analogs (e.g.,ciprostene, epoprostenol, carbacyclin, iloprost, beraprost); macrophageactivation preventers (e.g., bisphosphonates); HMG-CoA reductaseinhibitors (e.g., lovastatin, pravastatin, fluvastatin, simvastatin,cerivastatin); fish oils and omega-3-fatty acids; free-radicalscavengers/antioxidants (e.g., probucol, vitamins C and E, ebselen,retinoic acid (e.g., trans-retinoic acid), SOD mimics); agents affectingvarious growth factors including FGF pathway agents (e.g., bFGFantibodies, chimeric fusion proteins), PDGF receptor antagonists (e.g.,trapidil), IGF pathway agents (e.g., somatostatin analogs such asangiopeptin and ocreotide), TGF-β pathway agents such as polyanionicagents (heparin, fucoidin), decorin, and TGF-β antibodies, EGF pathwayagents (e.g., EGF antibodies, receptor antagonists, chimeric fusionproteins), TNF-α pathway agents (e.g., thalidomide and analogs thereof),thromboxane A2 (TXA2) pathway modulators (e.g., sulotroban, vapiprost,dazoxiben, ridogrel), protein tyrosine kinase inhibitors (e.g.,tyrphostin, genistein, and quinoxaline derivatives); MMP pathwayinhibitors (e.g., marimastat, ilomastat, metastat), and cell motilityinhibitors (e.g., cytochalasin B); antiproliferative/antineoplasticagents including antimetabolites such as purine analogs (e.g.,6-mercaptopurine), pyrimidine analogs (e.g., cytarabine and5-fluorouracil) and methotrexate, nitrogen mustards, alkyl sulfonates,ethylenimines, antibiotics (e.g., daunorubicin, doxorubicin, daunomycin,bleomycin, mitomycin, penicillins, cephalosporins, ciprofalxin,vancomycins, aminoglycosides, quinolones, polymyxins, erythromycins,tertacyclines, chloramphenicols, clindamycins, linomycins, sulfonamides,and their homologs, analogs, fragments, derivatives, and pharmaceuticalsalts), nitrosoureas (e.g., carmustine, lomustine) and cisplatin, agentsaffecting microtubule dynamics (e.g., vinblastine, vincristine,colchicine, paclitaxel, epothilone), caspase activators, proteasomeinhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin andsqualamine), and rapamycin, cerivastatin, flavopiridol and suramin;matrix deposition/organization pathway inhibitors (e.g., halofuginone orother quinazolinone derivatives, tranilast); endothelializationfacilitators (e.g., VEGF and RGD peptide); and blood rheology modulators(e.g., pentoxifylline).

Other examples of therapeutic agents include anti-tumor agents, such asdocetaxel, alkylating agents (e.g., mechlorethamine, chlorambucil,cyclophosphamide, melphalan, ifosfamide), plant alkaloids (e.g.,etoposide), inorganic ions (e.g., cisplatin), biological responsemodifiers (e.g., interferon), and hormones (e.g., tamoxifen, flutamide),as well as their homologs, analogs, fragments, derivatives, andpharmaceutical salts.

Additional examples of therapeutic agents include organic-solubletherapeutic agents, such as mithramycin, cyclosporine, and plicamycin.Further examples of therapeutic agents include pharmaceutically activecompounds, anti-sense genes, viral, liposomes and cationic polymers(e.g., selected based on the application), biologically active solutes(e.g., heparin), prostaglandins, prostcyclins, L-arginine, nitric oxide(NO) donors (e.g., lisidomine, molsidomine, NO-protein adducts,NO-polysaccharide adducts, polymeric or oligomeric NO adducts orchemical complexes), enoxaparin, Warafin sodium, dicumarol, interferons,chymase inhibitors (e.g., Tranilast), ACE inhibitors (e.g., Enalapril),serotonin antagonists, 5-HT uptake inhibitors, and beta blockers, andother antitumor and/or chemotherapy drugs, such as BiCNU, busulfan,carboplatinum, cisplatinum, cytoxan, DTIC, fludarabine, mitoxantrone,velban, VP-16, herceptin, leustatin, navelbine, rituxan, and taxotere.

Therapeutic agents are described, for example, in Buiser et al., U.S.patent application Ser. No. 11/311,617, filed on Dec. 19, 2005, andentitled “Coils”; DiMatteo et al., U.S. Patent Application PublicationNo. US 2004/0076582 A1, published on Apr. 22, 2004, and entitled “AgentDelivery Particle”; Pinchuk et al., U.S. Pat. No. 6,545,097; and Schwarzet al., U.S. Pat. No. 6,368,658, all of which are incorporated herein byreference.

While certain embodiments have been described, other embodiments arepossible.

As an example, while the formation of an embolic coil by winding aribbon on edge has been described, in some embodiments, a differentmethod can be used to form an embolic coil. For example, FIG. 13A showsa ribbon 400 with a side 404 having a relatively small thickness T7 anda side 408 having a relatively large thickness T8. As shown in FIG. 13A,ribbon 400 is wound around a mandrel 412 to form an embolic coil 416(FIGS. 13B and 13C). Ribbon 400 is not wound on edge, but instead iswound so that the thickness T9 of each winding (e.g., winding 420) ofembolic coil 416 is equal to thickness T8 of side 408. As shown in FIG.13C, ribbon 400 has a rectangular transverse cross-section with a widthW2 and a length L3 that is longer than width W2.

Embolic coil 416 has an inner diameter ID2 and an outer diameter OD3. Insome embodiments, inner diameter ID2 can be at least 0.001 inch (e.g.,at least 0.002 inch, at least 0.004 inch, at least 0.005 inch, at least0.01 inch, at least 0.015 inch, at least 0.02 inch, at least 0.025 inch,at least 0.03 inch, at least 0.035 inch) and/or at most 0.036 inch(e.g., at most 0.035 inch, at most 0.03 inch, at most 0.025 inch, atmost 0.02 inch, at most 0.015 inch, at most 0.01 inch, at most 0.005inch, at most 0.004 inch, at most 0.002 inch). In certain embodiments,outer diameter OD3 can be at least 0.003 inch (e.g., at least 0.005inch, at least 0.01 inch, at least 0.012 inch, at least 0.015 inch, atleast 0.02 inch, at least 0.03 inch, at least 0.035 inch) and/or at most0.038 inch (e.g., at most 0.035 inch, at most 0.03 inch, at most 0.02inch, at most 0.015 inch, at most 0.012 inch, at most 0.01 inch, at most0.005 inch).

As another example, while embolic coils formed of a wound ribbon havinga rectangular transverse cross-section have been described, in someembodiments, a ribbon with a different transverse cross-section can beused to form an embolic coil. As an example, FIG. 14 shows a sidecross-sectional view of an embolic coil 500 formed of windings of aribbon 510. As shown in FIG. 14, ribbon 510 has a square transversecross-section having a length L4 and a width W3 that are equal to eachother. As another example, FIG. 15 shows a side cross-sectional view ofan embolic coil 550 formed of windings of a ribbon 560. As shown in FIG.15, ribbon 560 has a diamond-shaped transverse cross-section.

As an additional example, in some embodiments, an embolic coil mayinclude consecutive windings that do not contact each other. In certainembodiments, an embolic coil may be formed entirely of windings that donot contact each other. For example, FIG. 16 shows an embolic coil 600formed of windings of a ribbon 610. As shown in FIG. 16, consecutivewindings of ribbon 610, such as windings 620 and 630, do not contacteach other. In some embodiments, consecutive windings of ribbon 610 canhave a space between them of at least 0.0005 inch (e.g., at least 0.001inch, at least 0.002 inch, at least 0.003 inch, at least 0.004 inch)and/or at most 0.005 inch (e.g., at most 0.004 inch, at most 0.003 inch,at most 0.002 inch, at most 0.001 inch). Embolic coil 600 has a pitchP2. In certain embodiments, pitch P2 can be at least 0.0015 inch (e.g.,at least 0.002 inch, at least 0.003 inch, at least 0.004 inch) and/or atmost 0.005 inch (e.g., at most 0.004 inch, at most 0.003 inch, at most0.002 inch). While windings of embolic coil 600 have approximately thesame amount of space between them, in some embodiments, an embolic coilcan be formed of a wound ribbon having windings with different amountsof space between them. The space between consecutive windings in anembolic coil can be used, for example, to accommodate a material thatenhances thrombosis, such as fibers that enhance thrombosis.

As a further example, in some embodiments, an embolic coil can have atleast two (e.g., three, four, five, 10, 15, 20) different outerdiameters. For example, FIG. 17 shows an embolic coil 700 formed ofwindings of a ribbon 710, such as windings 720 and 730. Embolic coil 700includes regions 740 of relatively small outer diameter and regions 750of relatively large outer diameter. In some embodiments, embolic coil700 can be formed by winding a ribbon around a mandrel having at leasttwo different outer diameters. In certain embodiments, embolic coil 700can be formed by winding a ribbon around a mandrel and then grindingdown certain regions of the ribbon to reduce the thickness of the ribbonin those regions, thereby forming regions of relatively small outerdiameter.

In regions 740, embolic coil 700 has an outer diameter OD4. In someembodiments, outer diameter OD4 can be at least 0.01 inch (e.g., atleast 0.02 inch) and/or at most 0.03 inch (e.g., at most 0.02 inch). Inregions 750, embolic coil 700 has an outer diameter OD5. In certainembodiments, outer diameter OD5 can be at least 0.015 inch (e.g., atleast 0.025 inch) and/or at most 0.035 inch (e.g., at most 0.025 inch).Embolic coil 700 further includes fibers 760 that are disposed betweenwindings of ribbon 710 in regions 740 of relatively small outerdiameter. Because fibers 760 are located in regions 740 of relativelysmall outer diameter, in some embodiments, embolic coil 700 can beaccommodated within a delivery device (e.g., a catheter) with arelatively low likelihood of substantial contact between fibers 760 andthe walls of the delivery device. This can be advantageous, for example,because if fibers 760 come into sufficient contact with the walls of thedelivery device, then fibers 760 can adhere to the walls, which cancomplicate the delivery of embolic coil 700 from the delivery device(e.g., to a target site). While embolic coil 700 is shown as includingfibers, in some embodiments, an embolic coil having at least twodifferent outer diameters may not include any fibers. Embolic coilshaving at least two different outer diameters are described, forexample, in Elliott et al., U.S. patent application Ser. No. 11/000,741,filed on Dec. 1, 2004, and entitled “Embolic Coils”, which isincorporated herein by reference.

As another example, while embodiments have been shown in which the pitchof an embolic coil is substantially the same in different regions of theembolic coil, in certain embodiments, the pitch of an embolic coil candiffer in different regions of the embolic coil. For example, someregions of an embolic coil can have a pitch of 0.002 inch, while otherregions of an embolic coil can have a pitch of 0.004 inch.

As an additional example, while a pushable embolic coil has been shown,in some embodiments, an embolic coil can alternatively or additionallybe a detachable embolic coil. For example, the embolic coil can betemporarily attached to a pusher wire. The embolic coil can be, forexample, mechanically detachable and/or chemically detachable. In someembodiments, the embolic coil can be electrolytically detachable. Incertain embodiments, the embolic coil can be a Guglielmi Detachable Coil(GDC) or an Interlocking Detachable Coil (IDC). Detachable embolic coilsare described, for example, in Twyford, Jr. et al., U.S. Pat. No.5,304,195, and Guglielmi et al., U.S. Pat. No. 5,895,385, both of whichare hereby incorporated by reference.

As a further example, in some embodiments, a saline flush can be used todeliver an embolic coil from a delivery device. In certain embodiments,the saline flush can be used in conjunction with a pusher wire.

As another example, in some embodiments, multiple (e.g., two, three,four) embolic coils can be delivered using one delivery device.

As an additional example, in certain embodiments, a treatment site canbe occluded by using embolic coils in conjunction with other occlusivedevices. For example, embolic coils can be used with embolic particlessuch as those described in Buiser et al., U.S. Patent ApplicationPublication No. US 2003/0185896 A1, published on Oct. 2, 2003, and inLanphere et al., U.S. Patent Application Publication No. US 2004/0096662A1, published on May 20, 2004, both of which are incorporated herein byreference. In some embodiments, embolic coils can be used in conjunctionwith one or more embolic gels. Embolic gels are described, for example,in Richard et al., U.S. Patent Application Publication No. US2006/0045900 A1, published on Mar. 2, 2006, and entitled “Embolization”,which is incorporated herein by reference.

As another example, in certain embodiments, an embolic coil can beloaded into a delivery device using an introducer sheath. For example,FIG. 18 illustrates the transfer of an embolic coil 800 from anintroducer sheath 810 into a catheter 820. A hub 830 located at theproximal end 840 of catheter 820 directs the placement of introducersheath 810. After introducer sheath 810 has been placed in hub 830, apusher 850 is used to push embolic coil 800 out of introducer sheath 810and into catheter 820.

As an additional example, in some embodiments, an embolic coil caninclude one or more radiopaque markers. The radiopaque markers can, forexample, be attached to one or more windings of the embolic coil.

Other embodiments are in the claims.

1. A wound ribbon in the shape of an embolic coil.
 2. The wound ribbonof claim 1, wherein the wound ribbon includes a first end that is notattached to a medical device or a medical device component, and a secondend that is not attached to a medical device or a medical devicecomponent.
 3. The wound ribbon of claim 1, wherein the wound ribbonincludes first and second windings.
 4. The wound ribbon of claim 3,wherein the first winding contacts the second winding.
 5. The woundribbon of claim 1, wherein the wound ribbon includes more than twowindings.
 6. The wound ribbon of claim 1, wherein the ribbon has apolygonal transverse cross-section.
 7. The wound ribbon of claim 1,wherein the ribbon has a rectangular transverse cross-section having awidth and a length that is longer than the width.
 8. The wound ribbon ofclaim 7, wherein the length of the rectangular transverse cross-sectionis at least 0.001 inch.
 9. The wound ribbon of claim 8, wherein thelength of the rectangular transverse cross-section is at most 0.005inch.
 10. The wound ribbon of claim 7, wherein the width of therectangular transverse cross-section is at least 0.0005 inch.
 11. Thewound ribbon of claim 10, wherein the width of the rectangulartransverse cross-section is at most 0.005 inch.
 12. The wound ribbon ofclaim 7, wherein a ratio of the length of the rectangular cross-sectionto the width of the rectangular cross-section is at least 1:1.
 13. Thewound ribbon of claim 12, wherein a ratio of the length of therectangular cross-section to the width of the rectangular cross-sectionis at most about 75:1.
 14. The wound ribbon of claim 1, furthercomprising at least one fiber.
 15. The wound ribbon of claim 14, whereinthe wound ribbon has a first winding and a second winding and the atleast one fiber is disposed between the first and second windings. 16.The wound ribbon of claim 1, wherein the wound ribbon comprises a metal.17. The wound ribbon of claim 1, wherein the wound ribbon comprises aradiopaque material.
 18. A method of making an embolic coil, the methodcomprising winding a ribbon into the shape of an embolic coil.
 19. Themethod of claim 18, wherein the embolic coil includes a first end and asecond end, and the method does not include attaching the first end orthe second end of the embolic coil to a medical device or a medicaldevice component.
 20. A first medical device, comprising: a tubular bodydefining a lumen; and at least one wound ribbon disposed within thelumen, wherein the at least one wound ribbon is in the shape of anembolic coil.
 21. The first medical device of claim 20, wherein thewound ribbon includes a first end that is not attached to a secondmedical device or a medical device component, and a second end that isnot attached to a second medical device or a medical device component.22. The medical device of claim 20, wherein the tubular body comprises acatheter.
 23. The medical device of claim 20, wherein the tubular bodycomprises an introducer sheath.
 24. A method, comprising: administeringat least one wound ribbon to a subject, wherein the at least one woundribbon is in the shape of an embolic coil.
 25. The method of claim 24,wherein the wound ribbon includes a first end that is not attached to amedical device or a medical device component, and a second end that isnot attached to a medical device or a medical device component.
 26. Themethod of claim 24, wherein the at least one wound ribbon comprises aplurality of wound ribbons.
 27. The method of claim 24, wherein themethod includes embolizing a lumen of a subject.
 28. A method of usingthe medical device of claim 20, the method comprising: inserting thetubular body into a lumen of a subject; and delivering the at least onewound ribbon into the lumen of the subject.